3967-32-6

Basic information

• Product Name: 5-(1-Methyl-4-Piperidyl)5H-Dibenzo
• Synonyms: 5-(1-Methyl-4-Piperidyl)5H-Dibenzo;5-(1-Methyl-4-Piperidyl)-5H-Dibenzo[a,d]-Cyclophen-5-ol;Cyproheptadine Related CoMpound C
• CAS NO: 3967-32-6
• Molecular Formula: C₂₁H₂₃NO
• Molecular Weight: 305.41342
• Mol File: 3967-32-6.mol
• Article Data: 4

Chemical Properties

• Melting Point: 166.7-167.7 °C(Solv: benzene (71-43-2); hexane (110-54-3))
• Boiling Point: 467.7°C at 760 mmHg
• Flash Point: 132.2°C
• Appearance: /
• Density: 1.158g/cm³
• Vapor Pressure: 1.5E-09mmHg at 25°C
• Refractive Index: 1.627
• PKA: 13.15±0.20(Predicted)
• CAS DataBase Reference: 5-(1-Methyl-4-Piperidyl)5H-Dibenzo(CAS DataBase Reference)
• NIST Chemistry Reference: 5-(1-Methyl-4-Piperidyl)5H-Dibenzo(3967-32-6)
• EPA Substance Registry System: 5-(1-Methyl-4-Piperidyl)5H-Dibenzo(3967-32-6)

Safety Data

• Hazardous Substances Data: 3967-32-6(Hazardous Substances Data)

Usage

Uses

5-(1-Methyl-4-piperidinyl)-5H-dibenzo[a,d]cyclohepten-5-ol is a derivative of Cyproheptadine (C989200) which is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties. Cyproheptadine is a 5-HT2/5-HT1C serotonin receptor antagonist; H1 histamine receptor antagonist; antipruritic.

InChI:InChI=1/C21H23NO/c1-22-14-12-18(13-15-22)21(23)19-8-4-2-6-16(19)10-11-17-7-3-5-9-20(17)21/h2-11,18,23H,12-15H2,1H3

Synthetic route

4-chloro-1-methylpiperidine (5570-77-4) + dibenzosuberenon (2222-33-5) → 5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6)

Conditions	Yield
Stage #1: 4-chloro-1-methylpiperidine With iodine; magnesium In tetrahydrofuran for 5h; Reflux; Inert atmosphere; Stage #2: With (trimethylsilyl)methylmagnesium chloride; lithium chloride; zinc(II) chloride In tetrahydrofuran; diethyl ether at 20℃; for 0.75h; Inert atmosphere; Stage #3: dibenzosuberenon In tetrahydrofuran; diethyl ether at 0℃; for 2h; Inert atmosphere;	99%
Stage #1: 4-chloro-1-methylpiperidine With magnesium In tetrahydrofuran at 60 - 65℃; for 1h; Inert atmosphere; Large scale; Stage #2: dibenzosuberenon In tetrahydrofuran at 5 - 20℃; for 1h; Temperature; Inert atmosphere; Large scale;

(1-methyl-4-piperidyl)magnesium chloride (63463-36-5) + dibenzosuberenon (2222-33-5) → 5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6)

Conditions	Yield
In tetrahydrofuran at 70℃;	76%

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → cyproheptadine (129-03-3)

Conditions	Yield
With formic acid at 100℃; for 2h;	99%
With hydrogenchloride; acetic acid at 120℃; for 2h;	83%
With formic acid for 1h; Heating; Yield given;

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → (+/-)-(5H)-1-methyl-4-(5H-dibenzocyclohepten-5-yl)piperidine (3973-59-9)

Conditions	Yield
With triethylsilane; boron trifluoride In dichloromethane at 0℃; for 3h;	74%

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (14051-46-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → 4-(4-Dibenzo[a,d]cyclohepten-5-ylidene-piperidin-1-yl)-butylamine (175692-31-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water 4: 80 percent / Na2CO3, KI / acetonitrile; dimethylformamide / Heating 5: 62 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h / Ambient temperature View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → 4-<4-(5H-dibenzocyclohepten-5-ylidene)piperidino>butanonitrile (141840-85-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water 4: 80 percent / Na2CO3, KI / acetonitrile; dimethylformamide / Heating View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → 7-(4-Dibenzo[a,d]cyclohepten-5-ylidene-piperidin-1-yl)-heptylamine (175692-29-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water 4: 99 percent / K2CO3 / acetonitrile / 90 °C 5: 81 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h / Ambient temperature View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → 7-(4-Dibenzo[a,d]cyclohepten-5-ylidene-piperidin-1-yl)-heptanenitrile (175692-23-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water 4: 99 percent / K2CO3 / acetonitrile / 90 °C View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → 4-Dibenzo[a,d]cyclohepten-5-ylidene-piperidine-1-carboxylic acid 1-chloro-ethyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → [4-(4-Dibenzo[a,d]cyclohepten-5-ylidene-piperidin-1-yl)-butyl]-((Z)-1-methylsulfanyl-2-nitro-vinyl)-amine

Conditions	Yield
Multi-step reaction with 6 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water 4: 80 percent / Na2CO3, KI / acetonitrile; dimethylformamide / Heating 5: 62 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h / Ambient temperature 6: acetonitrile / Heating View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → [7-(4-Dibenzo[a,d]cyclohepten-5-ylidene-piperidin-1-yl)-heptyl]-((Z)-1-methylsulfanyl-2-nitro-vinyl)-amine

Conditions	Yield
Multi-step reaction with 6 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water 4: 99 percent / K2CO3 / acetonitrile / 90 °C 5: 81 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h / Ambient temperature 6: acetonitrile / Heating View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → 1-[7-(4-Dibenzo[a,d]cyclohepten-5-ylidene-piperidin-1-yl)-heptyl]-3-[2-(2-guanidino-thiazol-4-ylmethylsulfanyl)-ethyl]-urea

Conditions	Yield
Multi-step reaction with 6 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water 4: 99 percent / K2CO3 / acetonitrile / 90 °C 5: 81 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h / Ambient temperature 6: 1) THF, 0 deg C, 2) THF, DMF, r.t., 24 h View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → N-[4-(2-{(Z)-1-[4-(4-Dibenzo[a,d]cyclohepten-5-ylidene-piperidin-1-yl)-butylamino]-2-nitro-vinylamino}-ethylsulfanylmethyl)-thiazol-2-yl]-guanidine

Conditions

Yield

Multi-step reaction with 7 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water 4: 80 percent / Na2CO3, KI / acetonitrile; dimethylformamide / Heating 5: 62 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h / Ambient temperature 6: acetonitrile / Heating 7: NEt3 / methanol / 75 °C View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → N-[4-(2-{(Z)-1-[7-(4-Dibenzo[a,d]cyclohepten-5-ylidene-piperidin-1-yl)-heptylamino]-2-nitro-vinylamino}-ethylsulfanylmethyl)-thiazol-2-yl]-guanidine

Conditions	Yield
Multi-step reaction with 7 steps 1: 83 percent / HOAc, conc. HCl / 2 h / 120 °C 2: Na2CO3 / 1,2-dichloro-ethane / 1) 0 deg C, 2) reflux 3: 1) CH3OH, 2) NaOH / 1) r.t., 15 min, 50 deg C, 15 min, 2) water 4: 99 percent / K2CO3 / acetonitrile / 90 °C 5: 81 percent / LiAlH4 / tetrahydrofuran; diethyl ether / 2 h / Ambient temperature 6: acetonitrile / Heating 7: NEt3 / methanol / 75 °C View Scheme

5-(1-methyl-4-piperidyl)-5H-dibenzocyclohepten-5-ol (3967-32-6) → cyproheptadine hydrochloride (969-33-5)

Conditions	Yield
With hydrogenchloride In ethanol; water at 90℃; for 1h; Large scale;

Upstream product

• 5570-77-4 4-chloro-1-methylpiperidine 
• 2222-33-5 dibenzosuberenon 
• 63463-36-5 (1-methyl-4-piperidyl)magnesium chloride 

Downstream Products

• 14051-46-8 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine 
• 969-33-5 cyproheptadine hydrochloride 
• 129-03-3 cyproheptadine 

Relevant articles and documents

Preparation method of cyproheptadine hydrochloride

The invention discloses a preparation method of cyproheptadine hydrochloride. According to the invention, the existing preparation method of the cyproheptadine hydrochloride is integrally improved, sothat the whole synthesis step is greatly simplified; and the prepared cyproheptadine hydrochloride has higher purity and yield, and the preparation method reduces the use of organic solvents and hazardous chemicals, simplifies the operation steps, reduces the operation difficulty, not only reduces the cost but also lightens the environmental burden, and is more beneficial to large-scale industrial production.

Synthesis and pharmacology of combined histamine H1-/H2-receptor antagonists containing diphenhydramine and cyproheptadine derivatives

The classical histamine H1-receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b-d, 10) were connected with a 2-guanidinothiazole containing structure (28) derived from the H2-receptor antagonist tiotidine in order to obtain combined H1/H2-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H1- and H2-receptor antagonist activity at the isolated guinea-pig ileum (H1) and the isolated guinea-pig right atrium (H2), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H1-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative (30-32, 34), however, cause a decrease of H2-receptor antagonist potency compared to the diphenhydramines (29a-d, 33a-d). Using nitroethenediamine as the polar group is apparently more favourable to H1- and H2-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H1-receptor antagonist moiety (29c, d) display the most potent H1- and H2-receptor antagonist effects. The presented concept is a very promising way to combine H1- and H2-receptor antagonist properties in one molecule.